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Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival

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Rogers, Matthew E., Kropf, P., Choi, B. S., Dillon, Rod, Podinovskaia, M., Bates, Paul and Müller, I. (2009) 'Proteophosophoglycans regurgitated by Leishmania-infected sand flies target the L-arginine metabolism of host macrophages to promote parasite survival'. PLoS Pathogens, Vol 5, Issue 8, e1000555.

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Abstract

All natural Leishmania infections start in the skin; however, little is known of the contribution made by the sand fly vector to the earliest events in mammalian infection, especially in inflamed skin that can rapidly kill invading parasites. During transmission sand flies regurgitate a proteophosphoglycan gel synthesized by the parasites inside the fly midgut, termed promastigote secretory gel (PSG). Regurgitated PSG can exacerbate cutaneous leishmaniasis. Here, we show that the amount of Leishmania mexicana PSG regurgitated by Lutzomyia longipalpis sand flies is proportional to the size of its original midgut infection and the number of parasites transmitted. Furthermore, PSG could exacerbate cutaneous L. mexicana infection for a wide range of doses (10-10,000 parasites) and enhance infection by as early as 48 hours in inflamed dermal air pouches. This early exacerbation was attributed to two fundamental properties of PSG: Firstly, PSG powerfully recruited macrophages to the dermal site of infection within 24 hours. Secondly, PSG enhanced alternative activation and arginase activity of host macrophages, thereby increasing L-arginine catabolism and the synthesis of polyamines essential for intracellular parasite growth. The increase in arginase activity promoted the intracellular growth of L. mexicana within classically activated macrophages, and inhibition of macrophage arginase completely ablated the early exacerbatory properties of PSG in vitro and in vivo. Thus, PSG is an essential component of the infectious sand fly bite for the early establishment of Leishmania in skin, which should be considered when designing and screening therapies against leishmaniasis. © 2009 Rogers et al.

Item Type: Article
Subjects: WA Public Health > Preventive Medicine > WA 108 Preventive health services. Preventive medicine. Travel Medicine.
WA Public Health > Health Problems of Special Population Groups > WA 395 Health in developing countries
QV Pharmacology > QV 38 Drug action.
QV Pharmacology > QV 4 General works
QX Parasitology > Protozoa > QX 70 Mastigophora. (e.g., Giardia. Trichomonas. Trypanosoma. Leishmania)
WB Practice of Medicine > Medical Climatology > WB 710 Diseases of geographic areas
QX Parasitology > Insects. Other Parasites > QX 505 Diptera
WB Practice of Medicine > Diagnosis > General Diagnosis > WB 141 General works
QX Parasitology > QX 45 Host-parasite relations
QX Parasitology > Insects. Other Parasites > QX 600 Insect control. Tick control
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 695 Parasitic diseases (General)
QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 680 Tropical diseases (General)
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 770 Therapy
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 755 Epidemiology
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 715 Visceral leishmaniasis
QX Parasitology > Insects. Other Parasites > QX 650 Insect vectors
QX Parasitology > QX 20 Research (General)
QX Parasitology > QX 4 General works
WA Public Health > Preventive Medicine > WA 110 Prevention and control of communicable diseases. Transmission of infectious diseases
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 765 Prevention and control
QV Pharmacology > QV 34 Experimental pharmacology (General)
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1371/journal.ppat.1000555
Depositing User: Mary Creegan
Date Deposited: 03 Jun 2010 15:08
Last Modified: 06 Feb 2018 12:59
URI: http://archive.lstmed.ac.uk/id/eprint/373

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